EP2316431B1 - Solid oral composition comprising a S1P receptor agonist and a sugar alcohol - Google Patents
Solid oral composition comprising a S1P receptor agonist and a sugar alcohol Download PDFInfo
- Publication number
- EP2316431B1 EP2316431B1 EP10184951.1A EP10184951A EP2316431B1 EP 2316431 B1 EP2316431 B1 EP 2316431B1 EP 10184951 A EP10184951 A EP 10184951A EP 2316431 B1 EP2316431 B1 EP 2316431B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- process according
- receptor agonist
- sugar alcohol
- alkyl
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Revoked
Links
- 239000000203 mixture Substances 0.000 title claims description 90
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 title claims description 48
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 title claims description 46
- 239000000018 receptor agonist Substances 0.000 title claims description 39
- 229940044601 receptor agonist Drugs 0.000 title claims description 39
- 150000005846 sugar alcohols Chemical class 0.000 title claims description 25
- 239000007787 solid Substances 0.000 title claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 47
- 235000010355 mannitol Nutrition 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 37
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical group CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 claims description 34
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 229930195725 Mannitol Natural products 0.000 claims description 31
- 239000000594 mannitol Substances 0.000 claims description 31
- 229960000556 fingolimod Drugs 0.000 claims description 27
- 239000002775 capsule Substances 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 8
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 45
- 229910052736 halogen Inorganic materials 0.000 description 42
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 29
- 125000005843 halogen group Chemical group 0.000 description 27
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- 125000000217 alkyl group Chemical group 0.000 description 21
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
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- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 6
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- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 5
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 5
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 5
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 241001440269 Cutina Species 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
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- 201000010099 disease Diseases 0.000 description 4
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- 125000003884 phenylalkyl group Chemical group 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
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- 238000009827 uniform distribution Methods 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
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Definitions
- the present invention relates to a process for producing a pharmaceutical composition in form of a solid formulation for oral administration in the form of a capsule, comprising
- Sphingosine-1 phosphate (hereinafter “S1P”) is a natural serum lipid.
- S1P receptors 8 known S1P receptors, namely S1P1 to S1P8.
- S1P receptor agonists have accelerating lymphocyte homing properties.
- S1P receptor agonists are immunomodulating compounds which elicit a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, evoking a generalized immunosuppression.
- Naive cells are sequestered, CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's patches (PP), and thus infiltration of cells into transplanted organs is inhibited.
- LN lymph nodes
- PP Peyer's patches
- S1P receptor agonists show structural similarities, which result in related problems in providing a suitable formulation.
- an S1P receptor agonist containing formulation which is well-adapted for oral administration in a solid form, e.g. as a tablet or capsule.
- EP 1 050 301 A mentions medicinal compositions comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and cyclodextrin which are for liquid administration.
- the present disclosure also provides a solid pharmaceutical composition suitable for oral administration, comprising a S1P receptor agonist and a sugar alcohol.
- compositions comprising a sugar alcohol provide formulations which are particularly well suited to the oral administration of S1P receptor agonists.
- the compositions provide a convenient means of systemic administration of S1P receptor agonists, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physicochemical and storage properties.
- the compositions obtainable according to the present invention may show a high level of uniformity in the distribution of the S1P receptor agonist throughout the composition, as well as high stability.
- the compositions, according to the present invention may be manufactured on high speed automated equipment, and thus do not require hand encapsulation.
- S1P receptor agonists are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives.
- S1P receptor agonists are, for example:
- a S1P receptor agonist for use in a combination may also be a selective S1P1 receptor, e.g. a compound which possesses a selectivity for the S1P1 receptor over the S1 P3 receptor of at least 20 fold, e.g. 100, 500, 1000 or 2000 fold, as measured by the ratio of EC50 for the S1P1 receptor to the EC50 for the S1P3 receptor as evaluated in a 35S-GTP ⁇ S binding assay, said compound having an EC50 for binding to the S1P1 receptor of 100 nM or less as evaluated by the 35S-GTP ⁇ S binding assay.
- Representative S1P1 receptor agonists are e.g. the compounds listed in WO 03/061567 , for instance a compound of formula or
- Acyl may be a residue R y -CO- wherein Ry is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or phenyl-C 1-4 alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.
- the carbon chain as R 1 is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy.
- the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted.
- the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.
- Preferred compounds of formula I are those wherein R 1 is C 13-20 alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R 1 is phenylalkyl substituted by C 6-14 -alkyl chain optionally substituted by halogen and the alkyl moiety is a C 1-6 alkyl optionally substituted by hydroxy. More preferably, R 1 is phenyl-C 1-6 alkyl substituted on the phenyl by a straight or branched, preferably straight, C 6-14 alkyl chain. The C 6-14 alkyl chain may be in ortho, meta or para, preferably in para.
- each of R 2 to R 5 is H.
- a preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol.
- a particularly preferred S1P receptor agonist of formula I which is the one used in the process according to the present invention, is FTY720, i.e. 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:
- a preferred compound of formula II is the one wherein each of R' 2 to R' 5 is H and m is 4, i.e. 2-amino-2- ⁇ 2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl ⁇ propane-1,3-diol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound B), e.g the hydrochloride.
- a preferred compound of formula III is the one wherein W is CH 3 , each of R" 1 to R" 3 is H, Z 2 is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound C), e.g. the hydrochloride.
- Compound C e.g. the hydrochloride.
- the R-enantiomer is particularly preferred.
- a preferred compound of formula IVa is the FTY720-phosphate (R 2a is H, R 3a is OH, X a is O, R 1a and R 1b are OH).
- a preferred compound of formula IVb is the Compound C-phosphate (R 2a is H, R 3b is OH, X a is O, R 1a and R 1b are OH, Y a is O and R 4a is heptyl).
- a preferred compound of formula V is Compound B-phosphate.
- a preferred compound of formula V is phosphoric acid mono-[(R)-2-amino-2-methyl-4-(4-pentyloxy-phenyl)-butyl]ester.
- a preferred compound of formula VIII is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbutan-1-ol.
- Examples of pharmaceutically acceptable salts of the compounds of formulae I to XIII include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals, such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine.
- the compounds and salts of the present disclosure encompass hydrate and solvate forms.
- Binding to S1 P receptors can be determined according to the following assays.
- S1P receptors and G i proteins are cloned, and equal amounts of 4 cDNAs for the EDG receptor, G i - ⁇ , G i - ⁇ and G i - ⁇ are mixed and used to transfect monolayers of HEK293 cells using the calcium phosphate precipitate method ( M. Wigler et al., Cell. 1977;11;223 and DS. Im et al., Mol. Pharmacol. 2000;57;753 ). Briefly, a DNA mixture containing 25 ⁇ g of DNA and 0.25 M CaCl 2 is added to HEPES-buffered 2 mM Na 2 HPO 4 .
- Subconfluent monolayers of HEK293 cells are poisoned with 25 mM chloroquine, and the DNA precipitate is then applied to the cells. After 4 h, the monolayers are washed with phosphate-buffered saline and refed media (90% 1:1 Dulbecco's modified essential media (DMEM):F-12 + 10% fetal bovine serum). The cells are harvested 48-72 h after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCl 2 , 1 EDTA, pH 7.4) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer.
- HME buffer in mM: 20 HEPES, 5 MgCl 2 , 1 EDTA, pH 7.4
- GTP ⁇ S binding experiments are performed as described by DS. Im et al., Mol. Pharmacol. 2000; 57:753.
- Ligand-mediated GTP ⁇ S binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCl, 10 MgCl 2 , pH 7.5) using 25 ⁇ g of a membrane preparation from transiently transfected HEK293 cells.
- Ligand is added to membranes in the presence of 10 ⁇ M GDP and 0.1 nM [ 35 S]GTP ⁇ S (1200 Ci/mmol) and incubated at 30°C for 30 min.
- Bound GTP ⁇ S is separated from unbound using the Brandel harvester (Gaithersburg, MD) and counted with a liquid scintillation counter.
- the composition especially the one obtained in the process of the invention, preferably contains 0.01 to 20% by weight of S1P receptor agonists, more preferably 0.1 to 10%, e.g. 0.5 to 5% by weight, based on the total weight of the composition.
- the sugar alcohol may act as a diluent, carrier, filler or bulking agent, and is e.g. mannitol (D-mannitol).
- the sugar alcohol is prepared from a spray-dried composition, e.g. mannitol composition, having a high specific surface area.
- a spray-dried composition e.g. mannitol composition
- the use of this type of mannitol composition may assist in promoting uniform distribution of the S1P receptor agonist throughout the mannitol in the compositon.
- a higher surface area may be achieved by providing a mannitol, preparation consisting of particles having a smaller mean size and/or a rougher surface on each particle.
- the use of a spray-dried mannitol e.g. with a mean particle size of 300 ⁇ m or less, has also been found to improve compressibility and hardness of tablets formed from the composition.
- the single point surface area of the sugar alcohol preparation is 1 to 7 m 2 /g, e.g. 2 to 6 m 2 /g or 3 to 5 m 2 /g.
- the mannitol preparation may suitably have a mean particle size of 100 to 300 ⁇ m, e.g. 150 to 250 ⁇ m and a bulk density of 0.4 to 0.6 g/mL, e.g. 0.45 to 0.55 g/mL.
- a suitable high surface area mannitol is Parteck M200, available commercially from E. Merck.
- composition obtainable according to the invention preferably contains 75 to 99.99% by weight of the sugar alcohol, more preferably 85 to 99.9%, e.g 90 to 99.5% by weight, based on the total weight of the composition.
- the composition preferably further comprises a lubricant.
- Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil such as hydrogenated castor oil (e.g. Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer, or a mixture of any of the above.
- the lubricant comprises magnesium stearate, hydrogenated castor oil or mineral oil. Colloidal silicon dioxide and polyethylene glycol are less preferred as the lubricant.
- the composition preferably contains 0.01 to 5% by weight of the lubricant, more preferably 1 to 3% by weight, e.g. about 2% by weight, based on the total weight of the composition.
- the composition may comprise one or more further excipients such as carriers, binders or diluents.
- the composition may comprise microcrystalline cellulose (e.g. Avicel®), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch (e.g. corn starch) or dicalcium phosphate, preferably in an amount of from 0.1 to 90 % by weight, e.g. 1 to 30% by weight, based on the total weight of the composition.
- a binder e.g. microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose is used, it is preferably included in an amount of 1 to 8 %, e.g.
- a binder increases the granule strength of the formulation, which is particularly important for fine granulations.
- Microcrystalline cellulose and methylcellulose are particularly preferred where a high tablet hardness and/or longer disintegration time is required. Hydroxypropyl cellulose is preferred where faster distintegration is required.
- xylitol may also be added as an additional binder, for example in addition to microcrystalline cellulose, e.g. in an amount up to 20% by weight of the sugar alcohol, e.g. xylitol.
- the composition further comprises a stabiliser, preferably glycine HCl or sodium bicarbonate.
- the stabiliser may be present in an amount of e.g. 0.1 to 30%, preferably 1 to 20% by weight.
- compositions in the form of a capsule are well-adapted for encapsulation into an orally administrable capsule shell, particularly a hard gelatin shell.
- compositions may be compacted into tablets.
- the tablets may optionally be coated, for instance with talc or a polysaccharide (e.g. cellulose) or hydroxypropylmethylcellulose coating.
- each unit dosage will suitably contain 0.5 to 10 mg of the S1P receptor agonist.
- compositions obtainable according to the invention may show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics may be determined, e.g. by measuring decomposition products by HPLC analysis after storage for particular times, at particular temperatures, e.g. 20°, 40° or 60°C.
- compositions of the present disclosure may be produced by standard processes, for instance by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes.
- Procedures which may be used are known in the art, e.g. those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986 , H. Sucker et al, Pharmazeutician Technologie, Thieme, 1991 , Hagers Handbuch der pharmazeutica fürtechnik, 4th Ed. (Springer Verlag, 1971 ) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970 ) or later editions.
- the present invention relates to the process for producing a pharmaceutical composition, comprising:
- the S1P receptor agonist e.g. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride
- the mixing step (a) may suitably comprise blending the S1P receptor agonist and the sugar alcohol, e.g. mannitol in any suitable blender or mixer for e.g. 100 to 400 revolutions.
- the process may be carried out by dry mixing the components.
- the milling step (b) may suitably comprise passing the mixture obtained in (a) through a screen, which preferably has a mesh size of 400 to 500 ⁇ m.
- Process step (a) may comprise the step of mixing the total amount of S1P receptor agonist at first with a low amount of sugar alcohol, e.g. from 5 to 25% by weight of the total weight of sugar alcohol, in order to form a pre-mix. Subsequently the remaining amount of sugar alcohol is added to the pre-mix.
- Step (a) may also comprise the step of adding a binder solution, e.g. methylcellulose and/or xylitol, e.g. an aqueous solution, to the mixture. Alternatively the binder is added to the mix dry and water is added in the granulation step.
- a binder solution e.g. methylcellulose and/or xylitol, e.g. an aqueous solution
- the milled mixture obtained in (b) may optionally be blended once more before mixing with the lubricant.
- the lubricant e.g. magnesium stearate
- the S1P receptor agonist is preferably first dry-mixed with the desired sugar alcohol, e.g. mannitol, and the obtained sugar alcohol/S1P receptor agonist mixture is then dry-mixed with a binder such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose. Water is then added and the mixture granulated, e.g. using an automated granulator. The granulation is then dried and milled.
- a binder such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose.
- an additional amount of binder may be added in step (c) to the mixture obtained in (b).
- the process may comprise a further step of tabletting or encapsulating the mixture obtained in (c), e.g. into a hard gelatin capsule using an automated encapsulation device.
- the capsules may be coloured or marked so as to impart an individual appearance and to make them instantly recognizable.
- the use of dyes can serve to enhance the appearance as well as to identify the capsules.
- Dyes suitable for use in pharmacy typically include carotinoids, iron oxides, and chlorophyll.
- the capsules of the invention are marked using a code.
- compositions obtainable according to the present invention are useful, either alone or in combination with other active agents, for the treatment and prevention of conditions e.g. as disclosed in US 5,604,229 , WO 97/24112 , WO 01/01978 , US 6,004,565 , US 6,274,629 and JP-14316985 .
- compositions are useful for:
- Micronized Compound A e.g. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride salt (FTY720), is screened and 116.7 g of the screened compound is mixed with 9683.3 g mannitol (Parteck M200 from E. Merck). The mixture is then milled in a Frewitt MGI device (Key International Inc. USA) using a 30 mesh screen. Magnesium stearate is screened using a 20 mesh screen and 200 g of the screened compound blended with the FTY720/mannitol mixture to produce a product composition.
- FTY720 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride salt
- the product composition is then compacted on a tablet press using a 7 mm die to form 120 mg tablets, each containing: Compound A, e.g. FTY720 * 1.4 mg Mannitol M200 116.2 mg Magnesium stearate 2.4 mg Total 120 mg * 1 mg of Compound A in free form is equivalent to 1.12 mg of FTY720.
- Compound A e.g. FTY720 * 1.4 mg Mannitol M200 116.2 mg
- Total 120 mg * 1 mg of Compound A in free form is equivalent to 1.12 mg of FTY720.
- example 2 the process of example 1 is repeated except that the magnesium stearate is replaced by Cutina® (hydrogenated castor oil).
- Cutina® hydrogenated castor oil
- Compound A e.g. FTY720, and mannitol (Parteck M200 from E. Merck) are each screened separately using an 18 mesh screen.
- 1.9 g screened FTY720 is mixed with 40 g screened mannitol for 120 revolutions in a blender at 32 rpm. The FTY720/mannitol mixture is then screened through a 35 mesh screen.
- the screened FTY720/mannitol mixture is added to a granulator along with a further 340.1 g mannitol and 12 g hydroxypropylcellulose.
- the mixture is mixed for 3 minutes. Water is then added at a rate of 100 ml/minute and the mixture granulated for 2 minutes. The granulation is transferred into a tray dryer and dried at 50°C for 150 minutes.
- the mixture is then milled in a Frewitt MGI device using a 35 mesh screen.
- Magnesium stearate is screened and 6 g of the screened compound is blended for 90 revolutions at 32 rpm with the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the S1P receptor agonist throughout the mannitol in the blend.
- each capsule contains: FTY720 * or 0.56 mg Mannitol M200 114.04mg Hydroxypropylcellulose 3.6 mg Magnesium stearate 1.8 mg Total 120 mg
- example 3 the process of example 3 is repeated except that the magnesium stearate is replaced by Cutina® (hydrogenated castor oil).
- Cutina® hydrogenated castor oil
- Micronized Compound A e.g. FTY720
- FTY720 is screened using a 400 ⁇ m (40 mesh) screen.
- 58.35 g of the screened compound is mixed with 4841.65 g mannitol (Parteck M200 from E. Merck) in a 25L Bohle bin blender for 240 blending revolutions.
- the mixture is then milled in a Frewitt MGI device using a 400 ⁇ m mesh screen, and the milled mixture is blended once more.
- Magnesium stearate is screened and 100 g of the screened compound is blended with the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the S1P receptor agonist throughout the mannitol in the blend.
- the product composition is then filled into size 3 hard gelatin shells on an Hoflinger & Karg 400 encapsulation device. 120 mg of the product composition is added to each capsule. Therefore each capsule contains: FTY720 * 1.4 mg Mannitol M200 116.2 mg Magnesium stearate 2.4 mg Total 120 mg
- capsules are manufactured using the components and in the amounts as described in Example 6a, but the FTY720 is first mixed with 14 mg mannitol (before screening). This mixture is then screened as described above. The screened mixture is then blended with the remaining mannitol and the magnesium stearate is added, followed by additional blending and filling into capsules.
- capsules are prepared as described in example 6, except that each capsule contains each component in the following amounts:
- Example 7 Example 8 FTY720 * 2.8 mg 5.6 mg Mannitol M200 114.8 mg 112 mg Magnesium stearate 2.4 mg 2.4 mg Total 120 mg 120 mg
- capsules are prepared as described in examples 6 to 8, except that the magnesium stearate is replaced in each case by Cutina® (hydrogenated castor oil).
- Cutina® hydrogenated castor oil
- capsules or tablets are prepared as described in examples 1 to 11, except that FTY720 is replaced in each case by 2-amino-2- ⁇ 2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl ⁇ propane-1,3-diol hydrochloride.
- Capsules containing the following ingredients are prepared, by weighing each component and mixing in a mortar, then filling into capsules:
- Example 23 Example 24 FTY720 5 mg 1 mg D-mannitol 83.7 mg 117 mg Corn starch 24 mg - Avicel® PH101 12 mg - Hydroxypropylcellulose 0.3 mg 7 mg Talc 3 mg 3 mg Lubri wax ®101 2 mg 2 mg Total 130 mg 130 mg
- Example 25 Example 26
- Example 27 FTY720 5g 10 g 100 g D-mannitol 991 g 986 g 897 g Methylcellulose SM-25 4g 4 g 3 g Total 1000 g 1000 g 1000 g
- the FTY720 and a proportion of the D-mannitol equal to twice the weight of the FTY720 are mixed in a Microspeed Mixer MS-5 type (Palmer, USA) for 2 minutes at 1200 rpm. The remaining D-mannitol is added to the mixture and mixed for another 2 minutes.
- 80 or 60 milliliters of 5% methylcellulose SM-25 solution is supplied from a hopper and granulated under the same conditions.
- the mixture is extruded through a screen with 0.4 mm apertures using an extruder RG-5 type.
- the extruded material is dried at 65°C by a fluidized-bed granulator STREA I Type (Patheon, Canada) and then sieved through a 24 mesh sieve. Fine particles which pass through a 60 mesh sieve are removed.
- the obtained fine granules are filled into capsules by a Zuma capsule-filling machine (100 mg per capsule).
- Tablets containing the following ingredients (in mg) are produced: Example 28 Example 29 Example 30 Example 31 FTY720 1 1 1 1 D-mannitol 62.3 62.3 62.0 62.0 Xylitol* 26.7(5.4) 26.7(5.4) 26.6 26.6 Methylcellulose - - 0.4 0.4 Microcrystalline cellulose 24.0 - 24.0 - Low-substituted Hydroxypropyl-cellulose - 24.0 - 24.0 Hydrogenated oil 6.0 6.0 6.0 6.0 Total 120.0 120.0 120.0 120.0 * The amount of xylitol indicated in brackets was used as a binder.
- FTY720, D-mannitol and xylitol are placed in a fluid-bed granulator (MP-01 model, Powrex), mixed for five minutes, and granulated under spray of binder solution, followed by drying till the exhaust temperature reaches 40°C.
- the granulation conditions are as shown below.
- Dried powder is passed through a 24-mesh sieve, added to the specified amount of filler and lubricant, and mixed in a mixer (Tubular Mixer, WAB) for three minutes to make the powder for compression.
- a mixer Trobular Mixer, WAB
- the resulting powder is compressed by a tabletting machine (Cleanpress correct 12 HUK, Kikushui Seisakusho) with a punch of 7 mm i.d. x 7.5 mm R at a compression force of 9800 N.
- Tablets containing the following ingredients (in mg) are produced: Ex. 32 Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39 FTY720 1 1 1 1 1 1 1 1 1 D-mannitol 116.6 114.2 104.6 114.2 104.6 116.6 115.4 113 magnesium stearate 2.4 2.4 2.4 2.4 - - - glycine HCl - 2.4 12 - - - - sodium bicarbonate - - - 2.4 12 - - - zinc stearate - - - - - - 2.4 - - silicone fluid - - - - - - - 3.6 - mineral oil - - - - - - - 6 Total 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0 12
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14163450.1A EP2769713A1 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S1P receptor agonist and a sugar alcohol |
SI200432283T SI2316431T1 (sl) | 2003-04-08 | 2004-04-06 | Trdna sestava za oralno odmerjanje, ki vsebuje agonista receptorja S1P in sladkorni alkohol |
CY20151101194T CY1117071T1 (el) | 2003-04-08 | 2015-12-29 | Στερεη συνθεση χορηγησης απο του στοματος η οποια περιλαμβανει εναν αγωνιστη υποδοχεα s1p και ενα αλκοολοσακχαρο |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46121503P | 2003-04-08 | 2003-04-08 | |
EP04725895A EP1613288B1 (en) | 2003-04-08 | 2004-04-06 | Solid pharmaceutical compositions comprising a s1p receptor agonist and a sugar alcohol |
EP08161161A EP2008650A3 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S 1 P receptor agonist and a sugar alcohol |
Related Parent Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08161161 Previously-Filed-Application | 2004-04-06 | ||
EP04725895A Division EP1613288B1 (en) | 2003-04-08 | 2004-04-06 | Solid pharmaceutical compositions comprising a s1p receptor agonist and a sugar alcohol |
EP04725895.9 Division | 2004-04-06 | ||
EP08161161A Division EP2008650A3 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S 1 P receptor agonist and a sugar alcohol |
EP08161161A Previously-Filed-Application EP2008650A3 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S 1 P receptor agonist and a sugar alcohol |
EP08161161.8 Division | 2008-07-25 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP14163450.1A Division EP2769713A1 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S1P receptor agonist and a sugar alcohol |
EP14163450.1A Division-Into EP2769713A1 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S1P receptor agonist and a sugar alcohol |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2316431A1 EP2316431A1 (en) | 2011-05-04 |
EP2316431B1 true EP2316431B1 (en) | 2015-09-30 |
Family
ID=32326722
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10184951.1A Revoked EP2316431B1 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S1P receptor agonist and a sugar alcohol |
EP04725895A Expired - Lifetime EP1613288B1 (en) | 2003-04-08 | 2004-04-06 | Solid pharmaceutical compositions comprising a s1p receptor agonist and a sugar alcohol |
EP10186307A Withdrawn EP2319502A1 (en) | 2003-04-08 | 2004-04-06 | Solid pharmaceutical compositions comprising a S1P receptor agonist and a sugar alcohol |
EP14163450.1A Withdrawn EP2769713A1 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S1P receptor agonist and a sugar alcohol |
EP08161161A Withdrawn EP2008650A3 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S 1 P receptor agonist and a sugar alcohol |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04725895A Expired - Lifetime EP1613288B1 (en) | 2003-04-08 | 2004-04-06 | Solid pharmaceutical compositions comprising a s1p receptor agonist and a sugar alcohol |
EP10186307A Withdrawn EP2319502A1 (en) | 2003-04-08 | 2004-04-06 | Solid pharmaceutical compositions comprising a S1P receptor agonist and a sugar alcohol |
EP14163450.1A Withdrawn EP2769713A1 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S1P receptor agonist and a sugar alcohol |
EP08161161A Withdrawn EP2008650A3 (en) | 2003-04-08 | 2004-04-06 | Solid oral composition comprising a S 1 P receptor agonist and a sugar alcohol |
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2004
- 2004-04-06 EP EP10184951.1A patent/EP2316431B1/en not_active Revoked
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- 2004-04-06 SI SI200431037T patent/SI1613288T1/sl unknown
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- 2004-04-06 KR KR1020057019066A patent/KR20050121712A/ko not_active Application Discontinuation
- 2004-04-06 RU RU2005134173/15A patent/RU2358716C2/ru not_active IP Right Cessation
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2005
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EP1201236A1 (en) * | 1999-06-30 | 2002-05-02 | Mitsubishi Pharma Corporation | Medicinal compositions for preventing or treating viral myocarditis |
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